Abstract: Human cytomegalovirus (HCMV) is a ubiquitous beta-herpes virus which causes serious disease in newborns and immunocompromised individuals. Similar to all other herpes viruses, HCMV causes a life-long, latent infection by establishing a state of quiescence in several cell types. The primary site of latent infection is thought to be myeloid lineage cells, including hematopoietic stem cells and mature monocytes. Using tissue culture models of latency, several HCMV encoded latency associated proteins have been identified, which appear to function at the cell surface. In order to more thoroughly understand the cellular changes necessary for establishing and maintaining the latent phenotype, we propose to use cell surface capture technology and mass-spectrometry to analyze the cell surface proteome of latently infected cells. This work builds upon an exciting breakthrough in latency modeling which allows for the isolation of large numbers of latently infected monocytes. The goals of our research strategy are two-fold: first, to compare the cell surface proteomes of mock and HCMV infected monocytes using mass-spectrometry, and second, to identify critical regulators of latency by antagonizing up- or down-regulated proteins on the cell surface. Since plasma membrane proteins control a variety of important cellular functions including signal transduction and transport, we expect this work to significantly advance our understanding of the mechanisms utilized to establish and maintain the latent phenotype. Furthermore, since cell surface proteins are the targets of a large percentage of currently marketed pharmaceuticals, this work has the potential to identify novel drug targets for the modulation of HCMV related disease.